NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling
Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not...
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| Veröffentlicht in: | Oncotarget 2016-09, Vol.7 (38), p.61036-61053 |
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| creator | Zhang, Jianchao Shao, Ximing Sun, Haiyan Liu, Ke Ding, Zhihao Chen, Juntao Fang, Lijing Su, Wu Hong, Yang Li, Huashun Li, Hongchang |
| description | Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC. |
| doi_str_mv | 10.18632/oncotarget.11062 |
| format | Article |
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Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.11062</identifier><identifier>PMID: 27506933</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Breast - metabolism ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Epithelial-Mesenchymal Transition ; Female ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Lentivirus ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation ; Nerve Tissue Proteins - metabolism ; Phenotype ; Prognosis ; Receptor, Notch1 - metabolism ; Research Paper ; Signal Transduction ; Stem Cells - metabolism ; Triple Negative Breast Neoplasms - metabolism ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Oncotarget, 2016-09, Vol.7 (38), p.61036-61053</ispartof><rights>Copyright: © 2016 Zhang et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-4b430f3433f69517d8354b1731f478409c3b7fb7cb856668f2b92265de6350b33</citedby><cites>FETCH-LOGICAL-c422t-4b430f3433f69517d8354b1731f478409c3b7fb7cb856668f2b92265de6350b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308634/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308634/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27915,27916,53782,53784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27506933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Jianchao</creatorcontrib><creatorcontrib>Shao, Ximing</creatorcontrib><creatorcontrib>Sun, Haiyan</creatorcontrib><creatorcontrib>Liu, Ke</creatorcontrib><creatorcontrib>Ding, Zhihao</creatorcontrib><creatorcontrib>Chen, Juntao</creatorcontrib><creatorcontrib>Fang, Lijing</creatorcontrib><creatorcontrib>Su, Wu</creatorcontrib><creatorcontrib>Hong, Yang</creatorcontrib><creatorcontrib>Li, Huashun</creatorcontrib><creatorcontrib>Li, Hongchang</creatorcontrib><title>NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC.</description><subject>Animals</subject><subject>Breast - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Proliferation</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Lentivirus</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Transplantation</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Phenotype</subject><subject>Prognosis</subject><subject>Receptor, Notch1 - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction</subject><subject>Stem Cells - metabolism</subject><subject>Triple Negative Breast Neoplasms - metabolism</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUclOHDEQtVAiQIQPyCXyMZcG7919iZQgkiARcglny_ZU9zhy2xPbgzSc-PRY7NShFlXVq-Uh9JGSEzoozk5TdKmaPEM9oZQotocO6SjGjknJ373yD9BxKX9JEyn6gY376ID1kqiR80N0d3X96xuOMJvqbyDscIZ5G0yFgusaMGx8M8Gb0C1QILr1bjEB12xi8dWniNPUIr8J0D2BYJvBlIqdiQ4ytjtsYjVziv7WxxlfperWuPg5mtDiD-j9ZEKB40d7hK6_n_85-9ld_v5xcfb1snOCsdoJKziZuOB8UqOk_WrgUljaczq1owQZHbf9ZHtnB6mUGiZmR8aUXIHikljOj9CXB9zN1i6wchDbEUFvsl9M3ulkvH6biX6t53SjJSft3aIBfH4EyOnfFkrViy8OQjAR0rZoOkgxkKaHVkofSl1OpWSYnsdQou_J0y_k6XvyWs-n1_s9dzxRxf8DZtibgg</recordid><startdate>20160920</startdate><enddate>20160920</enddate><creator>Zhang, Jianchao</creator><creator>Shao, Ximing</creator><creator>Sun, Haiyan</creator><creator>Liu, Ke</creator><creator>Ding, Zhihao</creator><creator>Chen, Juntao</creator><creator>Fang, Lijing</creator><creator>Su, Wu</creator><creator>Hong, Yang</creator><creator>Li, Huashun</creator><creator>Li, Hongchang</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160920</creationdate><title>NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling</title><author>Zhang, Jianchao ; Shao, Ximing ; Sun, Haiyan ; Liu, Ke ; Ding, Zhihao ; Chen, Juntao ; Fang, Lijing ; Su, Wu ; Hong, Yang ; Li, Huashun ; Li, Hongchang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-4b430f3433f69517d8354b1731f478409c3b7fb7cb856668f2b92265de6350b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Breast - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Proliferation</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Lentivirus</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Transplantation</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Phenotype</topic><topic>Prognosis</topic><topic>Receptor, Notch1 - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction</topic><topic>Stem Cells - metabolism</topic><topic>Triple Negative Breast Neoplasms - metabolism</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Jianchao</creatorcontrib><creatorcontrib>Shao, Ximing</creatorcontrib><creatorcontrib>Sun, Haiyan</creatorcontrib><creatorcontrib>Liu, Ke</creatorcontrib><creatorcontrib>Ding, Zhihao</creatorcontrib><creatorcontrib>Chen, Juntao</creatorcontrib><creatorcontrib>Fang, Lijing</creatorcontrib><creatorcontrib>Su, Wu</creatorcontrib><creatorcontrib>Hong, Yang</creatorcontrib><creatorcontrib>Li, Huashun</creatorcontrib><creatorcontrib>Li, Hongchang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Jianchao</au><au>Shao, Ximing</au><au>Sun, Haiyan</au><au>Liu, Ke</au><au>Ding, Zhihao</au><au>Chen, Juntao</au><au>Fang, Lijing</au><au>Su, Wu</au><au>Hong, Yang</au><au>Li, Huashun</au><au>Li, Hongchang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-09-20</date><risdate>2016</risdate><volume>7</volume><issue>38</issue><spage>61036</spage><epage>61053</epage><pages>61036-61053</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. 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| subjects | Animals Breast - metabolism Cell Line, Tumor Cell Movement Cell Proliferation Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic HEK293 Cells Humans Lentivirus Membrane Proteins - metabolism Mice Mice, Inbred BALB C Mice, Nude Neoplasm Metastasis Neoplasm Transplantation Nerve Tissue Proteins - metabolism Phenotype Prognosis Receptor, Notch1 - metabolism Research Paper Signal Transduction Stem Cells - metabolism Triple Negative Breast Neoplasms - metabolism Tumor Suppressor Protein p53 - metabolism |
| title | NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling |
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